US7847112B2 - Polymorphs of atovaquone and process of preparation thereof - Google Patents
Polymorphs of atovaquone and process of preparation thereof Download PDFInfo
- Publication number
- US7847112B2 US7847112B2 US10/569,036 US56903606A US7847112B2 US 7847112 B2 US7847112 B2 US 7847112B2 US 56903606 A US56903606 A US 56903606A US 7847112 B2 US7847112 B2 US 7847112B2
- Authority
- US
- United States
- Prior art keywords
- atovaquone
- ray diffraction
- crystalline
- diffraction peak
- value
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 title claims abstract description 87
- 229960003159 atovaquone Drugs 0.000 title claims abstract description 54
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title description 5
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 claims abstract description 5
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 claims abstract description 5
- 201000000317 pneumocystosis Diseases 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 238000002441 X-ray diffraction Methods 0.000 claims description 29
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 15
- 239000013078 crystal Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 6
- 239000012296 anti-solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- 238000001035 drying Methods 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- 230000001747 exhibiting effect Effects 0.000 claims 2
- 239000002245 particle Substances 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 241000233872 Pneumocystis carinii Species 0.000 abstract description 4
- 230000003473 anti-pneumocystis Effects 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- BSJMWHQBCZFXBR-UHFFFAOYSA-N 3-[4-(p-chlorophenyl)cyclohexyl]-4-hydroxy-1,2-naphthoquinone Chemical compound O=C1C(=O)C2=CC=CC=C2C(O)=C1C(CC1)CCC1C1=CC=C(Cl)C=C1 BSJMWHQBCZFXBR-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 10
- 238000010586 diagram Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
- C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/10—Separation; Purification; Stabilisation; Use of additives
Definitions
- the present invention relates to novel crystalline forms of anti Pneumocystis carinii compound (2-[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone) commonly known as Atovaquone and methods for producing the same.
- Pneumocystis carinii is a parasite, which has a natural habitat in lung tissue, in a host with normal immune system. Without treatment Pneumocystis carinii pneumonia is almost always fatal in immuncompromised host.
- U.S. Pat. No. 4,981,874 discloses the process of preparation and the activity of the Atovaquone.
- Polymorphs of Atovaquone are not reported yet.
- the term ‘polymorphs’ is meant to include different physical forms, crystalline/liquid crystalline/amorphous forms.
- Polymorphic studies have become very interesting and important as many active pharmaceutical ingredients exhibit polymorphism and some/one of the polymorphic form exhibit high bio-availability and also much better activity as compared to other polymorphs.
- U.S. Pat. No. 4,981,874 discloses the recrystallization/purification of Atovaquone using solvent acetonitrile.
- the polymorphic form obtained by this method is referred hereafter as Form I, characterized by an X-ray powder diffraction pattern having peaks at about 7.2, 11.04, 11.77, 19.34, 21.14, 24.61, 25.28, 28.4 ⁇ 0.2 degrees.
- the DSC thermogram of Form I shows a small endotherm at 197° C. followed by a sharp endotherm at 222° C.
- the present invention provides crystalline Atovaquone Form II, characterized by an X-ray powder diffraction pattern having peaks at about 7.02, 9.68, 10.68, 11.70, 14.25, 14.83, 18.60, 19.29, 23.32, 24.54 ⁇ 0.2 degrees.
- the DSC thermogram of Form II shows a small endotherm at 169° C. followed by a sharp endotherm at 222° C.
- the present invention also provides crystalline Atovaquone Form III, characterized by an X-ray powder diffraction pattern having peaks at about 6.99, 9.65, 12.67, 20.07, 20.65, 20.99, 21.88, 22.10, 25.56 ⁇ 0.2 degrees.
- the DSC thermogram of Form III shows characteristic sharp endotherm at 222° C.
- the present invention also provides a process for preparing Form I comprising of dissolution of crude Atovaquone in a solvent; adding anti-solvent to the solution, cooling the resultant solution and, collecting the crystals of Form I.
- the present invention also provides a process for converting crystalline Atovaquone Form I to Form II, comprising dissolution of Atovaquone Form I in a solvent by heating; cooling the resultant solution and, collecting the crystals of Form II.
- the present invention also provides a process for converting crystalline Atovaquone Form I to Form III, comprising dissolution of Atovaquone Form I in a solvent by heating; cooling the resultant solution and, collecting the crystals of Form III.
- the present invention also provides a process for preparing crystalline Atovaquone Form III, comprising dissolution of Atovaquone Form I in a solvent; adding anti-solvent to the solution, cooling the resultant solution and, collecting the crystals of Form III.
- compositions comprising therapeutically effective amount of polymorphs II and III of Atovaquone are also disclosed herein.
- a method of treating Pneumocystis carinii pneumonia comprising administering to a warm blooded animal an effective amount of a product-by-process composition of matter comprising polymorphic forms of Atovaquone is also envisaged as part of this invention.
- the present invention provides new crystal forms of Atovaquone.
- the discovery of new crystalline form of Active pharmaceutical ingredient will be advantageous with regard to improvement in performance of the product.
- the present invention also relates to the solid-state forms (i.e. Polymorphs) of Atovaquone that can be prepared by the methods described herein.
- a solvent is any liquid substance which has capacity to dissolve the organic compound Atovaquone, either at room temperature or higher.
- Antisolvent is an organic solvent in which organic compound such as Atovaquone has poor solubility.
- room temperature means a temperature from about 25° C. to 30° C.
- Atovaquone is prepared by the method described in U.S. Pat. No. 4,981,874 which is referred as Form I.
- Form I The X-ray powder diffraction diagram and DSC thermograms of Form I are shown in FIGS. 1 and 4 respectively.
- Atovaquone Form II is prepared from Form I by the method described below and the DSC thermogram, X-ray powder diffraction diagram of Form II are shown in FIGS. 2 and 5 respectively
- Atovaquone Form I Ig. of Atovaquone Form I was dissolved in 5 niL 1,4-Dioxane under reflux condition. The clear solution was allowed to cool to room temperature for 30 minutes and then cooled at 5° C. for 4 hours. The solid obtained was then recovered on Buchner funnel and dried to get Form II.
- Atovaquone Form III is prepared from Form I by the method described below and the DSC thermogram, X-ray powder diffraction diagram of Form III are shown in FIGS. 3 and 6 respectively
- Atovaquone Form I 0.5 g Atovaquone Form I was dissolved in 20 niL Acetone under reflux condition. 40 ml of water was maintained at 0° C. and to this cold water, the hot solution of the Atovaquone was added dropwise with stirring. The solution was maintained at the same temperature for 1 hr. The solid thus obtained was filtered and dried to get Form III.
- Atovaquone Form I was dissolved in 15 niL chloroform at room temperature. To this solution 20 mL of methanol was added drop wise under stirring at same temperature. The slurry obtained was stirred for 4 hrs. at the same temperature. The solid was filtered and dried to get Form III.
- Atovaquone Form I was dissolved in 80 mL diisopropyl ether under reflux condition. The solution was cooled to room temperature and maintained at same temperature for 4 hrs. The solid was filtered and dried to get Form III.
- FIG. 4 Shows the DSC Thermogram of Atovaquone Form I
- FIG. 5 Shows the DSC Thermogram of Atovaquone Form II
- FIG. 6 Shows the DSC Thermogram of Atovaquone Form III
- the polymorphic form I obtained by this method is characterized by an X-ray powder diffraction pattern ( FIG. 1 ) having peaks at about 7.2, 11.04, 11.77, 19.34, 21.14, 24.61, 25.28, 28.4 ⁇ 0.2 degrees.
- the DSC thermogram of Form I ( FIG. 4 ) shows a small endotherm at 197° C. followed by a sharp endotherm at 222° C.
- the present invention also provides crystalline Atovaquone Form III, characterized by an X-ray powder diffraction pattern ( FIG. 4 ) having peaks at about 6.99, 9.65, 12.67, 20.07, 20.65, 20.99, 21.88, 22.10, 25.56 ⁇ 0.2 degrees.
- the DSC thermogram of Form III ( FIG. 6 ) shows characteristic sharp endotherm at 222° C.
- compositions comprising therapeutically effective amount of polymorphs II and III of Atovaquone are prepared by conventional methods.
- a method of treating Pneumocystis carinii pneumonia comprising administering to a warm blooded animal an effective amount of a product-by-process composition of matter comprising polymorphic forms of Atovaquone is also envisaged as part of this invention
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2004/000213 WO2006008752A1 (fr) | 2004-07-16 | 2004-07-16 | Nouvelles formes polymorphes d'atovaquone, et leur procede de preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| US20060241311A1 US20060241311A1 (en) | 2006-10-26 |
| US7847112B2 true US7847112B2 (en) | 2010-12-07 |
Family
ID=34959816
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/569,036 Expired - Fee Related US7847112B2 (en) | 2004-07-16 | 2004-07-16 | Polymorphs of atovaquone and process of preparation thereof |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US7847112B2 (fr) |
| EP (1) | EP1768944A1 (fr) |
| JP (1) | JP2007510715A (fr) |
| KR (1) | KR20070033317A (fr) |
| CN (1) | CN1878741A (fr) |
| AU (1) | AU2004320912A1 (fr) |
| CA (1) | CA2549871A1 (fr) |
| EA (1) | EA200700332A1 (fr) |
| WO (1) | WO2006008752A1 (fr) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008122988A1 (fr) * | 2007-04-05 | 2008-10-16 | Cadila Healthcare Limited | Procédé de préparation de l'atovaquone et conversion de l'isomère cis en isomère trans |
| WO2009007991A2 (fr) * | 2007-04-19 | 2009-01-15 | Ipca Laboratories Limited | Nouveau procédé de préparation d'atovaquone et ses nouveaux intermédiaires |
| EP2213646A1 (fr) | 2007-06-26 | 2010-08-04 | Hetero Drugs Limited | Nouvelles formes cristallines d'atovaquone |
| BRPI0907463A2 (pt) | 2008-02-04 | 2019-09-24 | Pfizer Ltd | forma polimórfica de um derivado de [1,2,4] triazol [4,3-a] piridina para tratamento de doenças inflamatórias |
| WO2013098832A2 (fr) | 2011-09-08 | 2013-07-04 | Dishman Pharmaceuticals & Chemicals Ltd. | Nouveau procédé d'isolement et de purification sélectifs de 2-[4-(4-chlorophényl) cyclohexyl]-3-chloro-1,4-naphthoquinone et d'atovaquone |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2553647A (en) | 1946-03-20 | 1951-05-22 | Research Corp | Naphthoquinone antimalarials |
| EP0123238A2 (fr) * | 1983-04-14 | 1984-10-31 | The Wellcome Foundation Limited | Dérivés de naphtoquinone |
| US4981874A (en) | 1988-08-16 | 1991-01-01 | Latter Victoria S | Medicaments |
| US5856362A (en) * | 1994-09-02 | 1999-01-05 | Glaxo Wellcome Inc. | Medicaments for the treatment of toxoplasmosis |
-
2004
- 2004-07-16 CN CNA2004800328769A patent/CN1878741A/zh active Pending
- 2004-07-16 EP EP04806730A patent/EP1768944A1/fr not_active Withdrawn
- 2004-07-16 EA EA200700332A patent/EA200700332A1/ru unknown
- 2004-07-16 US US10/569,036 patent/US7847112B2/en not_active Expired - Fee Related
- 2004-07-16 KR KR1020067012150A patent/KR20070033317A/ko not_active Withdrawn
- 2004-07-16 CA CA002549871A patent/CA2549871A1/fr not_active Abandoned
- 2004-07-16 JP JP2006539076A patent/JP2007510715A/ja not_active Withdrawn
- 2004-07-16 AU AU2004320912A patent/AU2004320912A1/en not_active Abandoned
- 2004-07-16 WO PCT/IN2004/000213 patent/WO2006008752A1/fr not_active Ceased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2553647A (en) | 1946-03-20 | 1951-05-22 | Research Corp | Naphthoquinone antimalarials |
| EP0123238A2 (fr) * | 1983-04-14 | 1984-10-31 | The Wellcome Foundation Limited | Dérivés de naphtoquinone |
| US4981874A (en) | 1988-08-16 | 1991-01-01 | Latter Victoria S | Medicaments |
| US5856362A (en) * | 1994-09-02 | 1999-01-05 | Glaxo Wellcome Inc. | Medicaments for the treatment of toxoplasmosis |
Non-Patent Citations (1)
| Title |
|---|
| Louis F. Fieser, et al, Napthoquinone Antimalarials. IV-XI. Synthesis, 70 J. Am. Chem. Soc. 3174, 3188-91 (1948). * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2549871A1 (fr) | 2006-01-26 |
| AU2004320912A8 (en) | 2008-08-21 |
| US20060241311A1 (en) | 2006-10-26 |
| EP1768944A1 (fr) | 2007-04-04 |
| EA200700332A1 (ru) | 2007-08-31 |
| AU2004320912A1 (en) | 2006-04-27 |
| CN1878741A (zh) | 2006-12-13 |
| JP2007510715A (ja) | 2007-04-26 |
| KR20070033317A (ko) | 2007-03-26 |
| WO2006008752A1 (fr) | 2006-01-26 |
| WO2006008752A8 (fr) | 2006-06-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: USV LIMITED, INDIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TARUR, VENTAKA. R.;SATHE, DHANAJAY G.;MANTRIPRAGADA, NARAYANA R.;AND OTHERS;REEL/FRAME:018131/0584 Effective date: 20060428 |
|
| AS | Assignment |
Owner name: USV LIMITED, INDIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TARUR, V.R.;SATHE, D.J.;MANTRIPRAGADA, N.R.;AND OTHERS;REEL/FRAME:018284/0674 Effective date: 20060328 |
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| REMI | Maintenance fee reminder mailed | ||
| LAPS | Lapse for failure to pay maintenance fees | ||
| STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
| FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20141207 |